Sensing and interpreting extracellular signals in response to changes in the environment has been a fundamental feature of all life forms from the very beginning of evolution. To fulfil this function, networks of proteins have evolved, forming the intracellular signal transduction machinery. Whereas the appropriate control of these signal transduction systems is essential to homoeostasis, dysregulation of signalling leads to disease and often the death of the organism. The tribbles family of pseudokinases have emerged in recent years as key controllers of signal transduction via their interactions with several key kinases, ubiquitin ligases and transcription factors. In line with their role in regulating fundamentally important signalling pathways, members of the tribbles family have been implicated in the development of a range of human diseases. Whereas our mechanistic understanding of how these proteins contribute to disease is far from complete, the present paper attempts to summarize some of the most important recent developments in this field of research.